Treatment with an experimental oral tau aggregation inhibitor, hydromethylthionine mesylate (HMTM), led to a statistically significant reduction in an established biomarker of neurodegeneration in Alzheimer’s disease (AD) in the LUCIDITY phase 3 trial.
Blood concentrations of neurofilament light chain (NfL) showed a 93% reduction in change over 12 months in participants receiving HMTM at the target dose of 16 mg/day relative to the control group, which correlated significantly with a tau biomarker (p-tau 181) in blood and changes in cognitive test scores.
"This is the first tau aggregation inhibitor to reach the phase 3 stage of development and to produce results like this," Claude Wischik, PhD, executive chairman of TauRx Therapeutics, which is developing the drug, noted in an interview with Medscape Medical News.
"NfL is one of the best studied biomarkers in the business because it goes off the rails in a range of neurodegenerative disorders. In AD, it correlates with disease severity, and it tracks ongoing damage to neurons," Wischik explained.
Oral HMTM was designed to reduce tau pathology in AD, and the noted changes in NfL concentration by HMTM indicate a "direct impact on disease pathology," Wischik said.
The findings, from a prespecified blood biomarker analysis of the LUCIDITY phase 3 trial, were presented at the Alzheimer's Association International Conference (AAIC) 2023.
Support for Tau Inhibitor
Topline results from the LUCIDITY trial showed improvement in cognition over 18 months in participants with mild cognitive impairment (MCI) due to AD who were treated with a 16 mg/day dose of HMTM.
However, in an odd twist, participants in the control group who received a low dose of methylthioninium chloride (MTC) also showed cognitive improvement, as previously reported by Medscape Medical News.
As a result, HMTM 16 mg/day failed to reach its two primary endpoints — change from baseline on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) and the Alzheimer's Disease Cooperative Study/Activities of Daily Living Inventory (ADCS-ADL23) — relative to the MTC control group.
That’s likely because treatment with MTC, which is a variant of HMTM, unexpectedly achieved blood levels of active drug above the threshold needed to produce a clinical effect.
For the prespecified biomarker analysis reported at AAIC 2023, baseline and 12-month NfL plasma levels were available in 161 of 185 participants receiving HMTM 16 mg/day, 38 of 48 receiving HMTM 8 mg/day and 136 of 185 receiving MTC 8 mg/week.
Blood concentrations of NfL showed a statistically significant 93% reduction in change over 12 months in participants receiving HMTM at a dose of 16 mg/day relative to the control group (P = .0278), Wischik reported.
In addition, the p-tau 181 increase over 12 months "reduced to zero" with HMTM 16 mg/day and there was significant correlation between change in NfL and p-tau 181 concentration, he noted.
NfL reductions were significantly correlated with change in ADAS-Cog11 (P = .0038) and whole brain volume (P = .0359) over 24 months.
'Exciting' Biomarker Data
Commenting on the new data, Christopher Weber, PhD, director of global science initiatives at the Alzheimer's Association, told Medscape Medical News the phase 3 LUCIDITY results "suggest that HMTM could be a potential therapeutic for slowing down neurodegenerative processes in Alzheimer's disease."
"Plasma NfL is an interesting biomarker which is used more and more in clinical trials because it's noninvasive, accessible, and can assist in diagnosing and monitoring the disease in the early stages. Elevated NfL levels suggest that neurons are being affected in the brain, which could indicate the presence or progression of Alzheimer's disease," Weber told Medscape Medical News.
He said the biomarker data from the LUCIDITY study are "exciting."
"However, due to the relatively small sample size, we look forward to seeing additional research on HMTM in larger, and even more diverse cohorts to better understand the performance of this treatment and the role of NfL in Alzheimer's disease," Weber said.
Also providing outside perspective, Howard Fillit, MD, founding executive director of the Alzheimer's Drug Discovery Foundation (ADDF), noted that currently "there is a lot of effort in trying to address the abnormal tau that occurs in Alzheimer's disease."
The biomarker data from LUCIDITY show that HMTM "seems to markedly decrease the amount of NfL in plasma and there is some correlation with cognitive scores. The obvious unknown is whether these changes in plasma NfL will predict clinical benefit," Fillit told Medscape Medical News.
"This is an oral drug that has a good safety profile, and the mechanism of action makes sense, but we need to see the clinical data," Fillit said.
Final 2-year data from the LUCIDITY trial are expected to be released later this year.
In the United Kingdom, TauRx has entered an accelerated approval process for the drug, and the company said it plans to seek regulatory approval in the United States and Canada this year.
The study was funded by TauRx Therapeutics. Wischik is an employee of the University of Aberdeen, Aberdeen, Scotland, and TauRx Therapeutics. Weber and Fillit report no relevant financial relationships.
Alzheimer's Association International Conference (AAIC) 2023. Abstract 74962. Presented July 19, 2023.
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Cite this: Oral Tau Inhibitor Continues to Show Promise in Alzheimer’s - Medscape - Jul 21, 2023.